Experimental and clinical observations have supported the concept that neuropeptides play central roles in neurotransmission as well as the regulation of secretory functions of adenohypophysial, pancreatic, adrenalcortical and gut cells. Among the thirty or so neuropeptides that have been implicated in neuronal function in the mammalian central nervous system, several have also been suggested to function as neurotransmitters or neuromodulators primarily in afferent neurons.
NPY is a 36-residue, amidated peptide hormone which was first isolated from porcine brain and characterized. NPY is anatomically co-distributed and co-released with norepinephrine in and from sympathetic postganglionic neurons. Stimulation of the sympathetic nervous system under physiologic circumstances, e.g. exercise, cold exposure, surgical stress, etc., promotes an elevation of plasma concentrations of NPY. NPY is believed to participate along with norepinephrine in the regulation of vascular smooth muscle tone and maintenance of blood pressure. In addition to the post-synaptic action to increase vascular smooth muscle tone, NPY may also act presynaptically to inhibit both its own release and that of norepinephrine. This mechanism is similar to the presynaptic actions of norepinephrine that, acting through .alpha..sub.2 -adrenoreceptors, facilitates a local feedback regulation of the neurohumoral regulation of blood pressure. Over the past 30 years, knowledge of norepinephrine's role in regulation of blood pressure has resulted in increasing our understanding of cardiovascular regulation and the successful development of a variety of pharmacotherapeutic substances used clinically to treat disorders of cardiovascular function. These compounds are, in general, structural analogs of norepinephrine and serve as either agonists or antagonists of norepinephrine to treat hypotension or hypertension, respectively. These drugs, however useful, have not solved the problems of management of a variety of cardiovascular disorders.
An additional action of NPY is to decrease cardiac contractility (inotropy). This is an extremely important action of NPY, because it is known that, under many circumstances in which inotropy is decreased, diseases of life-threatening importance, e.g. congestive heart failure and cardiogenic shock, are associated with probable increased release of NPY into the blood. Prevention of NPY release, using a presynaptic NPY agonist, or NPY's action, using a postsynaptic NPY antagonist, may be beneficial in these disease states.
NPY has also been reported to produce coronary artery vasoconstriction and thereby may decrease myocardial blood flow resulting in myocardial ischemia. Such a circumstance can result in angina pectoris or, under more severe circumstances, may result in myocardial infarction and death. In recent years, several classes of drugs have proven effective in dilating coronary arteries to prevent such events. The use of analogs of NPY are expected to prove useful in treatment of such problems.
Porcine NPY has the formula: H-Tyr-Pro-Ser-Lys-Pro-Asp-Asn-Pro-Gly-Glu-Asp-Ala-Pro-Ala-Glu-Asp-Leu-Ala- Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH. sub.2. The formula of Human NPY has been deduced from clones obtained from total RNA by preparing cDNA and then employing DNA sequencing technologies and is accepted to be: H-Tyr-Pro-Ser-Lys-Pro-Asp-Asn-Pro-Gly-Glu-Asp-Ala-Pro-Ala-Glu-Asp-Met-Ala- Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH. sub.2.